Between 70-80% of rheumatoid arthritis (RA) patients produce antibodies against IgG, called rheumatoid factors (RF), suggesting that IgG is a common auto-antigen in the disease. Although anti-IgG antibodies are present in other diseases and during immune responses to pathogens, these are generally low affinity IgMs that are detectable only transiently. In RA however, RF are persistent, usually of moderate to high affinity, and may include multiple isotypes. In addition, IgM RF can show evidence of somatic hypermutation. We therefore hypothesize that activation of T cells reactive with IgG could mediate affinity maturation and/or isotype switching in RF-producing B cells in at least a subset of RA patients. To address this, we have developed class II MHC tetramers containing peptides of Ig kappa chain that are shown to bind increased numbers of CD4+ T cells in some RA patients. In specific aim 1, we propose to determine how tetramer reactivity relates to expression of particular class II HLA proteins, including subtypes of HLA-DR4 shown previously to be associated with RA. In specific aim 2, we will test whether increased tetramer reactivity found in some patients correlates with the presence of multiple isotype rheumatoid factors, and with several markers, which can be used to measure disease severity. These experiments should critically assess the hypothesis that T cell help is required for production of multiple isotype RF, and may distinguish subsets of patients based on tetramer reactivity that have different prognoses, and who might benefit from distinct treatment regimens.